High throughput rheological testing of materials

ABSTRACT

A library of materials is screened for viscosity. A library of materials is provided. The library is contacted with at least one capillary for applying a force through the materials. The relative flow resistance of the materials is measured in response to the force; and the materials in the library are ranked based on the monitored flow resistance.

TECHNICAL FIELD

The present invention generally relates to the field of materialscharacterization. In particular, the invention relates to highthroughput screens for evaluating the rheological properties of amaterial.

BACKGROUND OF THE INVENTION

Currently, there is substantial research activity directed toward thediscovery and optimization of polymeric materials for a wide range ofapplications. Although the chemistry of many polymers and polymerizationreactions has been extensively studied, it is, nonetheless, rarelypossible to predict a priori the physical or chemical properties aparticular polymeric material will possess or the precise compositionand architecture that will result from any particular synthesis scheme.Thus, characterization techniques to determine such properties are anessential part of the discovery process.

Combinatorial chemistry refers generally to methods for synthesizing acollection of chemically diverse materials and to methods for rapidlytesting or screening this collection of materials for desirableperformance characteristics and properties. Combinatorial chemistryapproaches have greatly improved the efficiency of discovery of usefulmaterials. For example, material scientists have developed and appliedcombinatorial chemistry approaches to discover a variety of novelmaterials, including for example, high temperature superconductors,magnetoresistors, phosphors and catalysts. See, for example, U.S. Pat.No. 5,776,359 to Schultz et al. In comparison to traditional materialsscience research, combinatorial materials research can effectivelyevaluate much larger numbers of diverse compounds in a much shorterperiod of time. Although such high-throughput synthesis and screeningmethodologies are conceptually promising, substantial technicalchallenges exist for application thereof to specific research andcommercial goals.

With the development of combinatorial techniques that allow for theparallel synthesis of arrays comprising a vast number of diverseindustrially relevant materials, there is a need for methods and devicesand systems to rapidly characterize the physical and mechanicalproperties of the samples that are synthesized, such as the viscosity orrelated rheological properties of a material. There is also a particularneed to reduce time involved in analyzing samples when transfer of thesample between locations is necessary. It would be especially attractiveto rapidly test a plurality of samples on a common substrate, withoutneeding to remove the samples from the substrate.

The characterization of materials using combinatorial methods has onlyrecently become known. Examples of such technology are disclosed, forexample, in commonly owned U.S. Pat. Nos. 6,182,499 (McFarland et al);6,175,409 B1 (Nielsen et al); 6,157,449 (Hajduk et al); 6,151,123(Nielsen); 6,034,775 (McFarland et al); 5,959,297 (Weinberg et al), allof which are hereby expressly incorporated by reference herein.

A high throughput viscometer is taught in U.S. application Ser. No.09/578,997, filed May 25, 2000 (“High Throughput Viscometer and Methodof Using the Same”) hereby expressly incorporated by reference herein.

SUMMARY OF THE INVENTION

In accordance with one preferred embodiment of the present invention, alibrary of materials is screened for rheological properties, such asviscosity. A force is applied to a library of materials while thematerials reside within their respective regions of a common substrate.The relative flow resistance of the materials is measured in response tothe force; and the materials in the library are analyzed and rankedbased on the monitored flow resistance.

In another preferred embodiment, a plurality of liquid samples isscreened for viscosity, where a library is provided having at least fourdifferent samples, and the viscosity of each of the samples is measuredserially at a throughput rate no greater than about 10 minutes persample.

In another preferred embodiment, a plurality of liquid samples isscreened for viscosity, where a library is provided having at least fourdifferent samples, and the viscosity of at least two of the samples ismeasured simultaneously at a throughput rate no greater than about 10minutes per library.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an analytical system in accordance with thepresent invention.

FIG. 1( a) is a magnified sectional view of a well of the system of FIG.1 having a probe located within the well.

FIG. 2 is a schematic of one preferred measuring instrument used in thepresent invention.

FIG. 3 is a schematic of another alternative analytical system inaccordance with the present invention.

FIGS. 4( a)–4(h) illustrate perspective views of several alternative tipportions for a plunger.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

I. Glossary

The following terms are intended to have the following general meaningsas they are used herein.

1. Substrate: A material or structure having a rigid or semi-rigidsurface. In many embodiments, the substrate will have physicallyseparate regions for different materials with, for example, dimples,wells, trenches, or the like. The regions will preferably be no greaterthan about 1 liter, and more preferably will be smaller than about 0.1liter, more preferably smaller than about 0.01 liter and still morepreferably smaller than about 0.001 liter. One preferred substrateuseful in accordance with the present invention is a microtiter platehaving a plurality of wells, and at least preferably 8×N wells, where Nis an integer 1 or higher. Another preferred substrate useful inaccordance with the present invention is a vial rack supporting aplurality of vials.

2. Viscosity: A measure of a resistance of a fluid to flow whensubjected to a force, and preferably one for inducing a shear stress.Reference herein to viscosity is not intended to exclude the employmentof viscosity measurements to the determination of other propertiesrecognized as interdependent upon the measurement of viscosity,including but not density, temperature dependent properties ofmaterials, pressure dependent properties of material, velocity/flowratedependent properties of materials or the like.

These and other aspects of the invention are to be considered exemplaryand non-limiting, and are discussed in greater detail below. The severalaspects of the characterization methods and systems disclosed andclaimed herein can be advantageously employed separately, or incombination to efficiently characterize a variety of materials, withparticular emphasis on polymeric materials. In preferred embodiments,these features are employed in combination to form a materialscharacterization system that can operate as a high-throughput screen ina materials science research program directed to identifying,characterizing or optimizing new or existing materials. Certaincharacterizing information—particularly those obtainable from thepresent invention are broadly useful for characterizing polymers andpolymerization reactions. As such, the particular materials and/ormechanisms disclosed herein should be considered exemplary of theinvention and non-limiting as to the scope of the invention, which maybe applicable in a variety of applications.

Combinatorial Approaches for Research

In a combinatorial approach for identifying or optimizing materials orpreparation conditions, a large compositional space (e.g., with respectto polymers, of monomers, comonomers, catalysts, catalyst precursors,solvents, initiators, additives, or of relative ratios of two or more ofthe aforementioned) and/or a large reaction condition space (e.g., oftemperature, pressure and reaction time) may be rapidly explored bypreparing libraries and then rapidly screening such libraries. By way ofillustration, polymer libraries can comprise, for example,polymerization product mixtures resulting from polymerization reactionsthat are varied with respect to such factors.

Combinatorial approaches for screening a library can include an initial,primary screening, in which product mixtures are rapidly evaluated toprovide valuable preliminary data and, optimally, to identify several“hits”—particular candidate materials having characteristics that meetor exceed certain predetermined metrics (e.g., performancecharacteristics, desirable properties, unexpected and/or unusualproperties, etc.). Such metrics may be defined, for example, by thecharacteristics of a known or standard material or preparation scheme.Because local performance maxima may exist in compositional spacesbetween those evaluated in the primary screening of the first librariesor alternatively, in process-condition spaces different from thoseconsidered in the first screening, it may be advantageous to screen morefocused libraries (e.g., libraries focused on a smaller range ofcompositional gradients, or libraries comprising compounds havingincrementally smaller structural variations relative to those of theidentified hits) and additionally or alternatively, subject the initialhits to variations in process conditions. Hence, a primary screen can beused reiteratively to explore localized and/or optimized compositionalspace in greater detail. The preparation and evaluation of more focusedlibraries can continue as long as the high-throughput primary screen canmeaningfully distinguish between neighboring library compositions orcompounds.

Once one or more hits have been satisfactorily identified based on theprimary screening, libraries focused around the primary-screen hits canbe evaluated with a secondary screen—a screen designed to provide (andtypically verified, based on known materials, to provide) chemicalprocess conditions that relate with a greater degree of confidence tocommercially-important processes and conditions than those applied inthe primary screen. In many situations, such improved“real-world-modeling” considerations are incorporated into the secondaryscreen at the expense of methodology speed (e.g., as measured by samplethroughput) compared to a corresponding primary screen. Particularcompositions, reactants, additives, processing conditions orpost-synthesis processing conditions having characteristics that surpassthe predetermined metrics for the secondary screen may then beconsidered to be “leads.” If desired, additional libraries focused aboutsuch lead materials can be screened with additional secondary screens orwith tertiary screens. Identified lead compositions, reactants,additives, processing conditions or post-synthesis processing conditionsmay be subsequently developed for commercial applications throughtraditional bench-scale and/or pilot scale experiments.

While the concept of primary screens and secondary screens as outlinedabove provides a valuable combinatorial research model, a secondaryscreen may not be necessary for certain chemical processes where primaryscreens provide an adequate level of confidence as to scalability and/orwhere market conditions warrant a direct development approach.Similarly, where optimization of materials having known properties ofinterest is desired, it may be appropriate to start with a secondaryscreen. In general, the systems, devices and methods of the presentinvention may be applied as either a primary, secondary or other screen,depending on the specific research program and goals thereof. See,generally, U.S. patent application Ser. No. 09/227,558 entitled“Apparatus and Method of Research for Creating and Testing NovelCatalysts, Reactions and Polymers”, filed Jan. 8, 1999 by Turner et al.,for further discussion of a combinatorial approach to polymer scienceresearch.

According to the present invention, methods, systems and devices aredisclosed that improve the efficiency and/or effectiveness of the stepsnecessary to characterize mechanical or physical properties of samplesor a plurality of samples (e.g., libraries of samples). In preferredembodiments, a property of a plurality of samples or of componentsthereof can be analyzed in a characterization system with an averagesample-throughput sufficient for an effective combinatorial scienceresearch program.

In accordance with one preferred embodiment of the present invention, anarray of materials is screened for viscosity. An array of materials isprovided. The array is contacted with at least one capillary forpermitting the materials to be drawn into the capillary. A first forceis applied to the materials while present in the capillary. The relativeflow resistance of the materials in the capillary is measured inresponse to the force; and the materials in the library of materials areranked or otherwise compared with each other or another material basedon the monitored flow resistance.

Various protocols may be employed involving some or all of theaforementioned steps. For example, a sample may be analyzed either withpreparation or without preparation. Additionally it should be recognizedthat sequences other than the order of steps listed above are possible,and the above listing is not intended as limiting.

As a general approach for improving the sample throughput for aplurality of samples (e.g., polymer samples), each of the stepsapplicable to a given characterization protocol can be optimized withrespect to time and quality of information, both individually and incombination with each other. Additionally or alternatively, each or someof such steps can be effected in a rapid-serial, parallel,serial-parallel or hybrid parallel-serial manner.

The throughput of a plurality of samples through a single step in acharacterization process is improved by optimizing the speed of thatstep, while maintaining—to the extent necessary—the information-qualityaspects of that step. Although conventional research norms, developed inthe context in which research was rate-limited primarily by thesynthesis of samples, may find such an approach less than whollysatisfactory, the degree of rigor can be entirely satisfactory for aprimary or a secondary screen of a combinatorial library of samples. Forcombinatorial research (and as well, for many on-line process controlsystems), the quality of information should be sufficiently rigorous toprovide for scientifically acceptable distinctions between the compoundsor process conditions being investigated, and for a secondary screen, toprovide for scientifically acceptable correlation (e.g., values or, forsome cases, trends) with more rigorous, albeit more laborious andtime-consuming traditional characterization approaches.

The throughput of a plurality of samples through a series of steps,where such steps are repeated for the plurality of samples, can also beoptimized. In one approach, one or more steps of the cycle can becompressed relative to traditional approaches or can have leading orlagging aspects truncated to allow other steps of the same cycle tooccur sooner compared to the cycle with traditional approaches. Inanother approach, the earlier steps of a second cycle can be performedconcurrently with the later steps of a first cycle. For example, in arapid-serial approach for characterizing a sample, sample delivery to asubstrate for a second sample in a series can be effected before orwhile the first sample in the series is being screened. As anotherexample, a screen of a second sample in a series can be initiated whilethe first sample in the series is being screened. These approaches, aswell as others, are discussed in greater detail below.

A characterization protocol for a plurality of samples can involve asingle-step process (e.g., direct measurement of a property of a sampleor of a component thereof). In a rapid-serial screen approach for asingle-step process, the plurality of samples and a single measuringinstrument or other apparatus are serially positioned in relation toeach other for serial analysis of the samples. In a parallel detectionapproach, two or more-measuring instruments or other apparatus areemployed to measure a property of two or more samples simultaneously.

In a serial-parallel approach, a property of a larger number of samples(e.g., four or more) is screened as follows. First, a property of asubset of the four or more samples (e.g., 2 samples) is screened inparallel for the subset of samples, and then serially thereafter, thesame property of another subset of four or more samples is screened inparallel. It will be recognized, of course, that plural measuringinstruments can be employed simultaneous, or plural measuringinstruments can be employed serially.

For characterization protocols involving more than one step,optimization approaches to effect high-throughput characterization canvary. As one example, a plurality of samples can be characterized with asingle characterization system (I) in a rapid-serial approach in whicheach of the plurality of samples (s₁, s₂, s₃ . . . s_(n)) are processedserially through the characterization system (I) with each of the stepseffected in series on each of the of samples to produce a serial streamof corresponding characterizing property information (p₁, p₂, p₃ . . .p_(n)). This approach benefits from minimal capital investment, and mayprovide sufficient throughput—particularly when the steps have beenoptimized with respect to speed and quality of information.

As another example, a plurality of samples can be characterized with twoor more instruments in a pure parallel (or for larger libraries,serial-parallel) approach in which the plurality of samples (s₁, s₂, s₃. . . s_(n)) or a subset thereof are processed through the two or moremeasurement systems (I, II, III . . . N) in parallel, with eachindividual system effecting each step on one of the samples to producethe property information (p₁, p₂, p₃ . . . p_(n)) in parallel. Thisapproach is advantageous with respect to overall throughput, but may beconstrained by the required capital investment.

In a hybrid approach, certain of the steps of the characterizationprocess can be effected in parallel, while certain other steps can beeffected in series. Preferably, for example, it may be desirable toeffect the longer, throughput-limiting steps in parallel for theplurality of samples, while effecting the faster, less limiting steps inseries. Such a parallel-series hybrid approach can be exemplified byparallel sample preparation of a plurality of samples (s₁, s₂, s₃ . . .s_(n)), followed by measuring a property with a single apparatus toproduce a serial stream of corresponding characterizing propertyinformation (p₁, p₂, p₃ . . . p_(n)). In another exemplaryparallel-series hybrid approach, a plurality of samples (s₁, s₂, s₃ . .. s_(n)) are prepared, measured and correlated in a slightly offset(staggered) parallel manner to produce the characterizing propertyinformation (p₁, p₂, p₃ . . . p_(n)) in the same staggered-parallelmanner.

Optimization of individual characterization steps with respect to speedand quality of information can improve sample throughput regardless ofwhether the overall characterization scheme involves a rapid-serial orparallel aspect (i.e., true parallel, serial-parallel or hybridparallel-series approaches). As such, the optimization techniquesdisclosed hereinafter, while discussed primarily in the context of arapid-serial approach, are not limited to such an approach, and willhave application to schemes involving parallel characterizationprotocols.

Material Samples

The materials screened in the present invention include polymericmaterials, organic materials, amorphous materials, crystallinematerials, macromolecular materials, small-molecule materials, inorganicmaterials, pure materials, mixtures of materials or the like.

The present invention may be used to screen or test most any flowablematerial that may be a commercial product itself or may be an ingredientor portion within a commercial product. Exemplary commercial products,which may be tested or may include ingredients that may be testedaccording to the present invention include pharmaceuticals, coatings,cosmetics, adhesives, inks, foods, crop agents, detergents, protectiveagents, lubricants and the like. Polyelectrolytes or polyampholytes mayalso be screened.

In a particularly preferred embodiment, the present invention isemployed for screening flowable samples. The invention thus hasparticular utility in connection with the screening of a number ofdifferent material forms including, for example, gels, oils, solvents,greases, creams, ointments, pastes, powders, films, particles, bulkmaterials, dispersions, suspensions, emulsions or the like. Theinvention can be used to analyze the resulting properties of aparticular flowable sample material or the relative or comparativeeffects that an additive or environmental condition has upon aparticular flowable sample material (e.g., the effect of a detergent, aflow modifier, or the like).

In another particularly preferred embodiment, the present invention isemployed for screening polymer samples, or plastic samples includingpolymers. Accordingly, unless otherwise stated, reference to screeningof polymers or other processing of polymers includes plasticsincorporating such polymers. The polymer sample can be a homogeneouspolymer sample or a heterogeneous polymer sample, and in either case,comprises one or more polymer components. As used herein, the term“polymer component” refers to a sample component that includes one ormore polymer molecules. The polymer molecules in a particular polymercomponent have the same repeat unit, and can be structurally identicalto each other or structurally different from each other. For example, apolymer component may comprise a number of different molecules, witheach molecule having the same repeat unit, but with a number ofmolecules having different molecular weights from each other (e.g., dueto a different degree of polymerization). As another example, aheterogeneous mixture of copolymer molecules may, in some cases, beincluded within a single polymer component (e.g., a copolymer with aregularly-occurring repeat unit), or may, in other cases, define two ormore different polymer components (e.g., a copolymer withirregularly-occurring or randomly-occurring repeat units). Hence,different polymer components include polymer molecules having differentrepeat units. It is possible that a particular polymer sample (e.g., amember of a library) will not contain a particular polymer molecule orpolymer component of interest. Blends of polymers may also be analyzedin accordance with the present invention.

In one embodiment, the polymer molecule of the polymer component ispreferably a non-biological polymer, though biological polymers may alsobe screened in accordance with the present invention. A non-biologicalpolymer is, for purposes herein, a polymer other than an amino-acidpolymer (e.g., protein) or a nucleic acid polymer (e.g.,deoxyribonucleic acid (DNA)). Though the employment of the presentinvention for screening of materials for use as biological implants iscontemplated. The non-biological polymer molecule of the polymercomponent is, however, not generally critical; that is, the systems andmethods disclosed herein will have broad application with respect to thetype (e.g., architecture, composition, synthesis method or mechanism)and/or nature (e.g., physical state, form, attributes) of thenon-biological polymer. Hence, the polymer molecule can be, with respectto homopolymer or copolymer architecture, a linear polymer, a branchedpolymer (e.g., short-chain branched, long-chained branched,hyper-branched), a cross-linked polymer, a cyclic polymer or a dendriticpolymer. A copolymer molecule can be a random copolymer molecule, ablock copolymer molecule (e.g., di-block, tri-block, multi-block,taper-block), a graft copolymer molecule or a comb copolymer molecule.

The particular composition of the polymer molecule is not critical, thematerial may be thermoplastic, thermoset or a mixture thereof. It may bea polycondensate, polyadduct, a modified natural polymer, or otherwise.Exemplary materials include polymers incorporating olefins, styrenes,acrylates, methacrylates, polyimides, polyamides, epoxies, silicones,phenolics, rubbers, halogenated polymers, polycarbonates, polyketones,urethanes, polyesters, silanes, sulfones, allyls, polyphenylene oxides,terphthalates, or mixtures thereof. Other specific illustrative examplescan include repeat units or random occurrences of one or more of thefollowing, without limitation: polyethylene, polypropylene, polystyrene,polyolefin, polyamide, polyimide, polyisobutylene, polyacrylonitrile,poly(vinyl chloride), poly(methyl methacrylate), poly(vinyl acetate),poly(vinylidene chloride), polytetrafluoroethylene, polyisoprene,polyacrylamide, polyacrylic acid, polyacrylate, poly(ethylene oxide),poly(ethyleneimine), polyamide, polyester, polyurethane, polysiloxane,polyether, polyphosphazine, polymethacrylate, and polyacetals.Polysaccharides are also preferably included within the scope ofpolymers. Exemplary naturally-occurring polysaccharides includecellulose, dextran, gums (e.g., guar gum, locust bean gum, tamarindxyloglucan, pullulan), and other naturally-occurring biomass. Exemplarysemi-synthetic polysaccharides having industrial applications includecellulose diacetate, cellulose triacetate, acylated cellulose,carboxymethyl cellulose and hydroxypropyl cellulose. In any case, suchnaturally-occurring and semi-synthetic polysaccharides can be modifiedby reactions such as hydrolysis, esterification, alkylation, or by otherreactions.

In typical applications, a polymer sample is a heterogeneous samplecomprising one or more polymer components, one or more monomercomponents and/or and an additional phase which may be a continuousfluid phase. In copolymer applications, the polymer sample can compriseone or more copolymers, a first comonomer, a second comonomer,additional comonomers, and/or a continuous fluid phase. The polymersamples can, in any case, also include other components, such ascatalysts, catalyst precursors (e.g., ligands, metal-precursors),solvents, initiators, additives, products of undesired side-reactions(e.g., polymer gel, or undesired homopolymer or copolymers) and/orimpurities. Typical additives include, for example, surfactants,fillers, reinforcements, flame retardants, colorants, environmentalprotectants, other performance modifiers, control agents, plasticizers,cosolvents and/or accelerators, among others. In th is regard, thepresent invention is particularly attractive for the screening ofaffects of variations of additives upon the characteristics of thematerial. The various components of the heterogeneous polymer sample canbe uniformly or non-uniformly dispersed in the continuous fluid phase.

In one embodiment, useful in connection with the screening of polymers,at a point prior to, during, or after depositing the sample onto thesubstrate, the sample is preferably treated to form a flowable sample,such as a polymer solution, a polymer emulsion, a polymer dispersion ora polymer that is liquid in the pure state (i.e., a neat polymer), or amelt. A polymer solution comprises one or more polymer componentsdissolved in a solvent. The polymer solution can be of a form thatincludes well-dissolved chains and/or dissolved aggregated micelles. Thesolvent can vary, depending on the application, for example with respectto polarity, volatility, stability, and/or inertness or reactivity.Typical solvents include, for example, tetrahydrofuran (THF), toluene,hexane, ethers, trichlorobenzene, dichlorobenzene, dimethylformamide,water, aqueous buffers, alcohols, etc. According to traditionalchemistry conventions, a polymer emulsion can be considered to compriseone or more liquid-phase polymer components emulsified (uniformly ornon-uniformly) in a liquid continuous phase, and a polymer dispersioncan be considered to comprise solid particles of one or more polymercomponents dispersed (uniformly or non-uniformly) in a liquid continuousphase. The polymer emulsion and the polymer dispersion can also beconsidered, however, to have the more typically employed meaningsspecific to the art of polymer science—of being anemulsion-polymerization product and dispersion-polymerization product,respectively. In such cases, for example, the emulsion polymer samplecan more generally include one or more polymer components that areinsoluble, but uniformly dispersed, in a continuous phase, with typicalemulsions including polymer component particles ranging in diameter fromabout 1 nm to about 500 nm, more typically from about 5 nm to about 300nm, and even more typically from about 40 nm to about 200 nm. Thedispersion polymer sample can, in such cases, generally include polymercomponent particles that are dispersed (uniformly or nonuniformly) in acontinuous phase, with typical particles having a diameter ranging fromabout 0.2 um to about 1000 um, more typically from about 0.4 um to about500 um, and even more typically from about 0.5 um to about 200 um.Exemplary polymers that can be in the form of neat polymer samplesinclude dendrimers, and siloxane, among others. The liquid polymersample can also be employed in the form of a slurry, a latex, a microgela physical gel, or in any other form sufficient for creating an arrayfor screening analysis as described and claimed herein. In some cases,polymer synthesis reactions (i.e., polymerizations) directly produceliquid samples. These may be bulk liquid polymers, polymer solutions, orheterogeneous liquid samples such as polymer emulsions, latices, ordispersions. In other cases, the polymer may be synthesized, stored orotherwise available for characterization in a non-liquid physical state,such as a solid state (e.g., crystalline, semicrystalline or amorphous),a glassy state or rubbery state. Hence, the polymer sample may need tobe dissolved, dispersed or emulsified to form a liquid sample byaddition of a continuous liquid-phase such as a solvent. The polymersample can, regardless of its particular form, have various attributes,including variations with respect to polarity, solubility and/ormiscibility.

In preferred applications, the polymer sample is a polymerizationproduct mixture. As used herein, the term “polymerization productmixture” refers to a mixture of sample components obtained as a productfrom a polymerization reaction. An exemplary polymerization productmixture can be a sample from a combinatorial library prepared bypolymerization reactions, or can be a polymer sample drawn off of anindustrial process line. In general, the polymer sample may be obtainedafter the synthesis reaction is stopped or completed or during thecourse of the polymerization reaction. Alternatively, samples of eachpolymerization reaction can be taken and placed into an intermediatearray of vessels at various times during the course of the synthesis,optionally with addition of more solvent or other reagents to arrest thesynthesis reaction or prepare the samples for analysis. Theseintermediate arrays can then be characterized at any time withoutinterrupting the synthesis reaction. It is also possible to use polymersamples or libraries of polymer samples that were prepared previouslyand stored. Typically, polymer libraries can be stored with agents toensure polymer integrity. Such storage agents include, for example,antioxidants or other agents effective for preventing cross-linking ofpolymer molecules during storage. Depending upon the polymerizationreaction, other processing steps may also be desired, all of which arepreferably automated. The polymerization scheme and/or mechanism bywhich the polymer molecules of the polymer component of the sample areprepared is not critical, and can include, for example, reactionsconsidered to be addition polymerization, condensation polymerization,step-growth polymerization, and/or chain-growth polymerizationreactions. Viewed from another aspect, the polymerization reaction canbe an emulsion polymerization or a dispersion polymerization reaction.Viewed more specifically with respect to the mechanism, thepolymerization reaction can be radical polymerization, ionicpolymerization (e.g., cationic polymerization, anionic polymerization),and/or ring-opening polymerization reactions, among others. Non-limitingexamples of the foregoing include, Ziegler-Natta or Kaminsky-Sinnreactions and various copolymerization reactions. Polymerization productmixtures can also be prepared by modification of a polymeric startingmaterials, by grafting reactions, chain extension, chain scission,functional group interconversion, or other reactions.

It will be appreciated that in certain embodiments, a polymer sample isformed in situ on a substrate, post synthesis treated in situ on asubstrate, or a combination thereof. Examples of such post synthesistreatment steps include for instance, heat treating, environmentalexposure (e.g. temperature moisture, radiation, chemicals, etc.), aged,or the like.

Sample Size

The sample size is not narrowly critical, and can generally vary,depending on the particular characterization protocols and systems usedto analyze the sample or components thereof. However, it will beappreciated that the present invention advantageously permits forattaining reliable data with relatively small samples. Typical samplesizes can range from about 0.1 microgram to about 1 gram, more typicallyfrom about 1 microgram to about 1000 micrograms, even more typicallyfrom about 5 micrograms to about 100 micrograms, and still moretypically from about 20 micrograms to about 50 micrograms.

When placed on a substrate for forming an array, as discussed hereinwith regard to sampling, the samples may be dispensed with any suitabledispensing apparatus (e.g. an automated micropipette or capillarydispenser, preferably with a heated tip). Each sample of the array isdispensed to an individually addressable region on the substrate.Preferably each sample occupies no more than about 1000 mm², morepreferably no more than about 100, more preferably no more than about 20mm² of planar area on a substrate surface, more preferably no more thanabout 5 mm², and shall more preferably no more than about 0.5 mm². Inapplications where the sample is disposed in a well, preferably thesample size does not exceed about 20 milligrams.

Accordingly, for some applications, the individual samples are eachtypically no greater than about 20 ml, more preferably no greater thanabout 5 ml and still more preferably no greater than about 0.5 ml.

Libraries of Samples

A plurality of samples comprises 2 or more samples that are physicallyor temporally separated from each other—for example, by residing indifferent regions of a substrate, in different sample containers, byhaving a membrane or other partitioning material positioned betweensamples, or otherwise. The plurality of samples preferably comprises 4or more samples and more preferably 8 or more samples. Four samples canbe employed, for example, in connection with experiments having onecontrol sample and three samples varying (e.g., with respect tocomposition or process conditions as discussed above) to berepresentative of a high, a medium and a low-value of the variedfactor—and thereby, to provide some indication as to trends. Foursamples are also a minimum number of samples to effect a serial-parallelcharacterization approach, as described above (e.g., with two detectorsoperating in parallel). Eight samples can provide for additionalvariations in the explored factor space. Moreover, eight samplescorresponds to the number of parallel polymerization reactors in thePPR-8™, being selectively offered as one of the Discovery ToolS™ ofSymyx Technologies, Inc. (Santa Clara, Calif.), which can be used toprepare polymers for screening in accordance with the present invention.Higher numbers of samples can be investigated, according to the methodsof the invention, to provide additional insights into largercompositional and/or process space. In some cases, for example, theplurality of samples can be 15 or more samples, preferably 20 or moresamples, more preferably 40 or more samples and even more preferably 80or more samples. Such numbers can be loosely associated with standardconfigurations of other parallel reactor configurations for synthesizingpolymers for screening herein (e.g., the PPR-48™, Symyx Technologies,Inc.) and/or of standard sample containers (e.g., 96-well microtiterplate-type formats). Moreover, even larger numbers of samples can becharacterized according to the methods of the present invention forlarger scale research endeavors. Hence, the number of samples can be 150or more, 400 or more, 500 or more, 750 or more, 1,000 or more, 1,500 ormore, 2,000 or more, 5,000 or more and 10,000 or more samples. As such,the number of samples can range from about 2 samples to about 10,000samples, and preferably from about 8 samples to about 10,000 samples. Inmany applications, however, the number of samples can range from about80 samples to about 1500 samples. In some cases, in which processing ofsamples using typical 96-well microtiter-plate formatting is convenientor otherwise desirable, the number of polymer samples can be 96*N, whereN is an integer ranging from about 1 to about 100. For manyapplications, N can suitably range from 1 to about 20, and in somecases, from 1 to about 5.

The plurality of samples can be a library of samples. A library ofsamples comprises an array of two or more different samples spatiallyseparated—preferably on a common substrate, or temporally separated.Candidate samples (i.e., members) within a library may differ in adefinable and typically predefined way, including with regard tochemical structure, processing (e.g., synthesis) history, mixtures ofinteracting components, post-synthesis treatment, purity, etc. Thesamples are spatially separated, preferably at an exposed surface of thesubstrate, such that the array of samples are separately addressable forcharacterization thereof. The two or more different samples can residein sample containers formed as wells in a surface of the substrate. Thenumber of samples included within the library can generally be the sameas the number of samples included within the plurality of samples, asdiscussed above. In general, however, not all of the samples within alibrary of samples need to be different samples. When process conditionsare to be evaluated, the libraries may contain only one type of sample.Typically, however, for combinatorial chemistry research applications,at least two or more, preferably at least four or more, even morepreferably eight or more and, in many cases most, and allowably each ofthe plurality of samples in a given library of samples will be differentfrom each other. Specifically, a different sample can be included withinat least about 50%, preferably at least 75%, preferably at least 80%,even more preferably at least 90%, still more preferably at least 95%,yet more preferably at least 98% and most preferably at least 99% of thesamples included in the sample library. In some cases, all of thesamples in a library of samples will be different from each other.

In one embodiment, preferably at least eight samples are provided in alibrary on a substrate and at least about 50% of the samples included inthe library are different from each other. More preferably, the libraryincludes at least 16 samples and at least 75% of the samples included inthe library are different from each other. Still more preferably, thelibrary includes at least 48 samples and at least 90% of the samplesincluded in the library are different from each other.

The substrate can be a structure having a rigid or semi-rigid surface onwhich or into which the array of samples can be formed or deposited. Thesubstrate can be of any suitable material, and preferably includesmaterials that are inert with respect to the polymer samples ofinterest, or otherwise will not materially affect the mechanical orphysical characteristics of one sample in an array relative to another.Exemplary polymeric materials that can be suitable as a substratematerial in particular applications include polyimides such as Kapton™,polypropylene, polytetrafluoroethylene (PTFE) and/or polyetheretherketone (PEEK), among others. The substrate material is alsopreferably selected for suitability in connection with known fabricationtechniques. Stainless steel or another metal, or ceramics such assilicon including polycrystalline silicon, single-crystal silicon,sputtered silicon, and silica (SiO₂) in any of its forms (quartz, glass,etc.) are preferred substrate materials. Other known materials (e.g.,silicon nitride, silicon carbide, metal oxides (e.g., alumina), mixedmetal oxides, metal halides (e.g., magnesium chloride), minerals,zeolites, and ceramics) may also be suitable for a substrate material insome applications. As to form, the sample containers formed in, at or ona substrate can be preferably, but are not necessarily, arranged in asubstantially flat, substantially planar surface of the substrate. Thesample containers can be formed in a surface of the substrate asdimples, spots, wells, raised regions, trenches, or the like.Non-conventional substate-based sample containers, such as relativelyflat surfaces having surface-modified regions (e.g., selectivelywettable regions) can also be employed. The overall size and/or shape ofthe substrate is not limiting to the invention. The size and shape canbe chosen, however, to be compatible with commercial availability,existing fabrication techniques, and/or with known or later-developedautomation techniques, including automated sampling and automatedsubstrate-handling devices. The substrate is also preferably sized to beportable by humans. The substrate can be thermally insulated,particularly for high-temperature and/or low-temperature applications.

In preferred embodiments, the substrate is designed such that theindividually addressable regions of the substrate can act aspolymerization or other suitable reaction vessels for preparing aproduct mixture, as well as sample containers for the in-situ analysisof two or more different samples during subsequent characterizationthereof. Glass-lined, 96-well, 384-well and 1536-well microtiter-typeplates, fabricated from stainless steel and/or aluminum, are preferredsubstrates for a library of liquid or polymer samples. The choice of anappropriate specific substrate material and/or form for certainapplications will be apparent to those of skill in the art in view ofthe guidance provided herein.

The library of materials can be a combinatorial library of productmixtures. Libraries can comprise, for example, product mixturesresulting from reactions that are varied with respect to, for example,reactant materials (e.g., monomers, comonomers), catalysts, catalystprecursors, initiators, additives, the relative amounts of suchcomponents, reaction conditions (e.g., temperature, pressure, reactiontime), post-synthesis treatment, or any other factor affectingpolymerization or material properties. Design variables forpolymerization reactions are well known in the art. See generally,Odian, Principles of Polymerization, 3rd Ed., John Wiley & Sons, Inc.(1991). A library of polymer samples may be prepared in arrays, inparallel polymerization reactors or in a serial fashion. Exemplarymethods and apparatus for preparing polymer libraries—based oncombinatorial polymer synthesis approaches—are disclosed in copendingU.S. patent application Ser. No. 09/211,982 of Turner et al. filed Dec.14, 1998, copending U.S. patent application Ser. No. 09/227,558 ofTurner et al. filed Jan. 8, 1999, copending U.S. patent application Ser.No. 09/235,368 of Weinberg et al. filed Jan. 21, 1999, and copendingU.S. provisional patent application Ser. No. 60/122,704 entitled“Controlled, Stable Free Radical Emulsion and Water-BasedPolymerizations”, filed Mar. 9, 1999 by Klaerner et al. See also, PCTPat. Application WO 96/11878.

The libraries can be advantageously characterized directly, withoutbeing isolated, from the reaction vessel in which the sample wasprepared or synthesized.

While such methods are preferred for a combinatorial approach toresearch, they are to be considered exemplary and non-limiting. As notedabove, the particular samples characterized according to the methods andwith the apparatus disclosed herein can be from any source, including,but not limited to polymerization product mixtures or other liquids,including those resulting from combinatorial synthesis approaches.

Analytical Instrument

The protocols for characterizing one or more samples preferably furthercomprise determining a property of interest from the detected propertybased upon the resulting viscosity measurements. The physically-detectedproperties, can be correlated to properties of interest. Such propertiesof interest include, without limitation, rheological properties such asviscosity, viscoelasticity (e.g., shear dependent viscoelasticity),shear thinning, shear thickening, yield, stress and the like. Otherproperties of interest may include, without limitation, melt index,thermal degradation, aging characteristics, weight-average molecularweight, number-average molecular weight, viscosity-average molecularweight, peak molecular weight, approximate molecular weight,polydispersity index, molecular-weight-distribution shape, relative orabsolute component concentration, chemical composition, conversion,concentration, mass, hydrodynamic radius, radius of gyration, chemicalcomposition, amounts of residual monomer, presence and amounts of otherlow-molecular weight impurities in samples, particle or molecular size,intrinsic viscosity, molecular shape, molecular conformation, and/oragglomeration or assemblage of molecules. The correlation between ameasured viscosity and a determined property of interest can be based onmathematical models and/or empirical calibrations. Such correlationmethods are generally known in the art.

The aforementioned characterizing properties of interest can, oncedetermined, be mathematically combined in various combinations toprovide figures of merit for various properties or attributes ofinterest. Other combinations of the fundamental characterizationproperties of interest will be apparent to those of skill in the art.

Referring to FIG. 1, the system 10 of the present invention includes aforce applicator 12 for applying a force to a sample 14 in an array ofsamples on a substrate 16, and a device 18 for measuring the response ofthe sample to the force. More specifically, and with reference to FIG.2, a preferred instrument 20 of the present invention includes atranslatable plunger 22 with a tip portion 24 for applying a pressureupon a sample. It will be appreciated that samples are provided to thesubstrate in any suitable manner, such as by a robot or an otherwiseautomated fluid dispenser.

In one preferred embodiment, the translatable plunger is drivinglyconnected to a suitable motor for driving the plunger 22 serially intothe samples. The motor may be directly connected to the plunger or itmay be connected to intermediate linkage in direct driving engagementwith the plunger. By way of example, a suitable robotic system isemployed, such as an XYZ robot arm available commercially from supplierssuch Cavro Scientific Instruments, Inc. (Sunnyvale, Calif.). Such devicehas multiple axis range of motion, and more preferably at least motionin the orthogonal x, y, z coordinate axes system. One or more suitablestepper motors or servo motors may be employed in addition to oralternative to the CAVRO robotic system. A microprocessor or other likecomputer is programmed for directing the robot relative to therespective locations of members of an array. Alternatively an automaticauto-sampler instrument may be suitably adapted for use such asauto-samplers commercially available from Agilent Technologies.Optionally, the same or a different robot may be employed fortransferring samples to the substrate and thereafter analyzing them.

By way of example, in a particularly preferred embodiment, a robot 28 isprogrammably employed (e.g., using one or more types of software, suchas IMPRESSIONIST™, or EPOCH™, available from Symyx Technoloies, Inc.)for rapid serial testing of a plurality of samples in an array. Forinstance, the robot 28 directs the plunger 22 to a first sample. Theplunger 22 is passed through the first sample and then removed. Theplunger optionally is then washed or flushed to remove residue from aprevious sample or the plunger is optionally replaced if disposableplungers are used. The process is repeated for a second sample andconsecutively thereafter with the remaining samples to be tested.

It will be appreciated that the robot may itself include a motor fordriving the plunger. Alternatively, the robot may be employed for twoaxis translation of the plunger with one or more additional motors orother suitable actuators for directly driving the plunger in the thirdof the orthogonal axes. A motor may also be employed as desired forsuitable rotational translation.

In yet another embodiment it is possible to rest a substrate ofspecimens upon a mounting stage (or load cell) that is translatablerelative to a fixed capillary or plunger. It is also possible to employa translatable mounting stage or load cell and a capillary or plunger incombination. In this regard, and with further reference to FIG. 2, asuitable substrate holder 30 is employed for positioning the samplesheld by the substrate 16 relative to the plunger 22. For instance, asubstrate such as a microtiter plate might nestingly reside in theholder 30, which may itself be associated with a load cell.Alternatively, as illustrated in FIG. 3 (without limitation upon theembodiment in which it might be employed) a stage 32 might be employedfor receiving a substrate. The stage 32 preferably includes a suitablestructure 34 for securing the substrate in place during sampling, suchas a clamp, a mechanical fastener arrangement or the like.

Regardless of the drive system employed, it should be sufficient toinduce a testing force of about 0.001 KN to about 100 KN and morepreferably at least about 0.1 KN to about 20 KN. It shall be understood,however that a variety of testing forces may be induced depending uponthe drive system or other factors. Further, preferably the plunger speedranges from about 0.001 to about 1500 mm/min and more preferably about0.01 to about 1000 mm/min, and still more preferably about 1 to about100. The drive system is capable of operating at temperatures to atleast about 400° C.

The force measurement device may include one or more suitable measuringdevices including conventional load cells, pressure transducers,sensors, detectors or the like. A single measuring device may beemployed to measure the relative displacement of a sample in response tothe force induced by the plunger.

Referring to FIG. 1, for rapid serial testing a highly preferred systememploys one or more load cells 30 upon which a substrate 16 is placed. Asingle plunger 22 is employed, with the robot consecutively relocatingthe plunger 22 and samples in the array relative to each other. The loadcell may be a single load cell common to each sample or well. The loadcell may be a single load cell with individually addressable regionscorresponding to each sample or well. Each sample may be assigned itsown load cell or a plurality of load cells may be used wherein each isassigned to a plurality of samples.

Alternatively or in addition to the other measuring devices, the plungeritself may include a suitable measuring device. The plunger or plungersmay be fitted with a load cell, pressure transducer or any othersuitable measuring device.

While the present invention lends itself especially well to rapid serialtesting, parallel testing (i.e., testing of two or more samplessimultaneously) may be employed alternatively or in combination withrapid serial testing. Of course, suitable modifications will beappropriate. For instance, a plurality of plungers can be employed forsimultaneous positioning relative to the array of samples. Preferably, asuitable pressure transducer or other sensor or detector is employed formeasuring resistance to flow in a sample of an individual plunger inview of a known applied force. In this manner, multiple samples can betested at once.

Any suitable art disclosed measuring device may be employed. Typically,measuring devices such as load cells, pressure transducers and the likecan be chosen from many commercially available devices depending onwhere it is desirable to mount or place the devices.

The measurement device preferably is equipped to output a signal orreadout correlating with a measurement. The output might be visuallyreadable from the device itself (e.g., an integrated LED, LCD or likedisplay). It might be outputted as an electrical signal that isconverted to a voltage for driving a control unit, microprocessor or thelike, or otherwise communicates with a computer into which the measuringdevice output is entered for sorting, storing, comparing, analyzing orthe like. Such computer may be separate from or integrated with anycontrol or computer used for driving the plunger, or for deliveringsamples to a substrate.

The plungers of the present invention are specifically adapted for usewith fluids in individual members of sample libraries on a substrate. Asdiscussed, one highly preferred embodiment employs a microtiter plate ora suitable receptacle or vial supporting rack as the substrate.Accordingly, a preferred plunger for the application is configured forapplying force to a fluid (e.g., liquid) in the respective wells of themicrotiter plate or wells of the receptacles (e.g., vials). Moreparticularly, referring to FIGS. 1( a) and 4(a), the preferred plungeris configured at a tip portion 24 to substantially matingly fit within awell 44 of the microtiter plate 16. Close tolerances are desired betweenthe outer wall 80 of the plunger tip portion 24 and an inner wall 82 ofa well 44. Preferably, the tolerances are such that any parasiticconductance of fluid in gaps between the plunger outer wall and wellinner wall (or elsewhere in the plunger) is statistically negligiblerelative to the primary fluid conductance observed.

The plunger employed in the present invention thus may employ any of anumber of suitable tip portion configurations that permit fluid passageinto and through at least a portion of it. By way of example, referringagain to FIGS. 1( a) and 4(a), one tip portion 24 might be constructedto permit passage of fluid through a central axial bore 86. The tipportion thus has an outer diameter that approximates the diameter ofeach well of a microtiter plate. Accordingly, the wall defining themicrotiter plate well serves as a guide surface for the tip portion. Inthis example the tip portion preferably is a sufficiently rigidstructure to reduce the potential for incidental deflection of the tipportion upon force application, which might affect the integrity of themeasurement. However, it is possible that the tip portion may be made inwhole or in part of a more flexible material, so that sealing may beaccomplished between the plunger and the wall of a well, therebydirecting the fluid through the central bore 86.

In another embodiment, shown in FIG. 4( b), the tip portion isconfigured to have an outer wall 48 that is spaced from the inner wall44(b) of a well over some or all of its outer periphery. The spacing ismaintained through the use of a suitable positioning device for keepingthe tip portion centered in the well. More preferably, a spacerstructure is employed, such as a plurality of radial spacing projections(e.g., fins) 50. Referring to the example of FIGS. 4( b) and 4(d),though configurations with one or two radial spacing projections arepossible, more preferably, three or more radial projections are employedto help provide axial stability.

Any of a number of other configurations may be employed including aplurality of axial bores as shown in FIG. 4( c), elongated slot shapedpassageways as shown in FIG. 4( f), passageways that vary in size orconfiguration along the axis of the plunger as shown in FIG. 4( e),composites of the examples of FIGS. 4( a)–4(f) or other configurations.The plunger preferably is made of a suitable metal, plastic or ceramicmaterial, and may be coated or uncoated over some or all of its surfacethat is to contact the test fluid. Preferably it is made of an epoxy orepoxy based material. It may be coated or uncoated, smooth or roughenedor otherwise treated for modifying its surface characteristics over someor all of its inner or outer surfaces. The dimensions of the overallplunger are not critical. However, in one preferred embodiment, for usein screening samples directly in a microtiter plate, the ratio of lengthto diameter ranges from about 5:1 to about 100:1. It may be desirable insome instances to control the ratio of the relative amount of surfacearea as between a lead face of a tip portion and the area of the wallsdefining the axial passageway. For example, such ratio might range fromabout greater than 20:1, and more preferably about 50:1.

It may be preferable for the tips to include vertical walls on its outerperiphery or on its inner periphery defining one or more bores. It mayalso be preferable for the bores to of the tips to be the same size incircumstances where more than one tip is used or where a tip includesmultiple bores.

In still other alternatives shown in FIGS. 4( g)–4(h), bores may betapered to have progressively smaller cross-sectional areas further upthe tip.

As can be appreciated from the above, in operation, the rheological orviscosity properties of a fluid, and preferably an array of fluidsamples can be measured while the samples are physically located on asubstrate. For instance, in a preferred embodiment, samples aresynthesized in an array of wells and then tested in the same array ofwells Alternatively, the samples may be prepared elsewhere and thentransferred to the array of wells, such as by manually or using anautomated sampler as described herein. According to either of theseembodiments one or more automatic systems (e.g., robots) may be used forpreparation of samples, testing of samples or both.

While the sample is in the well, and without the need to withdraw itfrom the well, the plunger is moved up or down in the fluid at a knownvelocity, which may be variable, but is preferably constant. The plungertip portion is configured so that as it moves through the fluid, thefluid on the leading side (i.e., the side that is forward relative tothe plunger movement direction), is forced to flow through thepassageways defined in or about the plunger. The fluid thus flows fromthe leading side to the trailing side of the plunger as the plunger isadvanced, all the while remaining resident within the well of thesubstrate. Preferably, the flow of the fluid continues until a dynamicequilibrium is reached between the pressure in the plunger and thepressure outside the plunger.

The pressure required to create the flow is produced by the downwardforce of plunger. In turn, the response of the fluid is measured by theload cell or a suitable sensor located in sensing relationship beneaththe substrate, directly or indirectly on the plunger, or both. From themeasurements alone, it is possible to obtain comparative data as betweensamples of an array. Such data may be compiled and samples grouped by orotherwise ranked in order of their relative performance. Taking intoaccount known information such as the plunger velocity, geometry ofcontainer, sample size, channel size and the like, quantitativerheological properties can also be determined or calculated.

Sample-Throughput

For methods directed to characterizing a plurality of samples, aproperty of each of the samples or of one or more components thereof isdetected—serially or in a parallel, serial-parallel or hybridparallel-serial manner—at an average sample throughput of not more thanabout 10 minutes per sample, though slower throughput is within thepresent invention. As used in connection herewith, the term “averagesample throughput” refers to the sample-number normalized total(cumulative) period of time required to detect a property of two or morepolymer samples with a characterization system. The total, cumulativetime period is delineated from the initiation of the characterizationprocess for the first sample, to the detection of a property of the lastsample or of a component thereof, and includes any interveningbetween-sample pauses in the process. The sample throughput is morepreferably not more than about 8 minutes per sample, even morepreferably not more than about 4 minutes per sample, still morepreferably not more than about 2 minutes per sample and even still morepreferably about 15 to 30 seconds per sample. Depending on the qualityresolution of the characterizing information required, the averagesample throughput can be not more than about 1 minute per sample, and ifdesired, not more than about 30 seconds per sample, not more than about20 seconds per sample or not more than about 10 seconds per sample, andin some applications, not more than about 5 seconds per sample and notmore than about 1 second per sample. Sample-throughput values of lessthan 4 minutes, less than 2 minutes, less than 1 minute, less than 30seconds, less than 20 seconds and less than 10 seconds are demonstratedin the examples. The average sample-throughput preferably ranges fromabout 10 minutes per sample to about 10 seconds per sample, morepreferably from about 8 minutes per sample to about 10 seconds persample, even more preferably from about 4 minutes per sample to about 10seconds per sample and, in some applications, most preferably from about2 minutes per sample to about 10 seconds per sample.

A sample-throughput of 10 minutes per sample or less is important for anumber of reasons. Systems that detect a property of a sample or of acomponent thereof at the aforementioned sample throughput rates can beemployed effectively in a combinatorial research program. From acompletely practical point of view, the characterization rates are alsoroughly commensurate with reasonably-scaled sample library synthesisrates. It is generally desirable that combinatorial screening systems,such as the characterization protocols disclosed herein, operate withroughly the same sample throughput as combinatorial synthesisprotocols—to prevent a backlog of uncharacterized product samples.Hence, to illustrate, because moderate scale polymer-synthesis systems,such as the Discovery Tools™ PPR-48™ (Symyx Technologies, Santa ClaraCalif.), can readily prepare polymer libraries with a sample-throughputof about 100 polymer samples per day, a screening throughput of about 10minutes per sample or faster is desirable. Higher throughput synthesissystems demand higher characterization throughputs. The preferred higherthroughput values are also important with respect to process controlapplications, to provide near-real time control data.

Additionally, as shown in connection with the examples provided herein,the characterization of samples at such throughputs can offersufficiently rigorous quality of data, to be useful for scientificallymeaningful exploration of the materials, compositions, formulations,compounds and/or reaction conditions.

Hence, the average sample-throughput can range, in preferred cases, fromabout 10 minutes per sample to about 8 minutes per sample, from about 8minutes per sample to about 2 minutes per sample, from about 2 minutesper sample to about 1 minute per sample, from about 1 minute per sampleto about 30 seconds per sample and from about 1 minute per sample toabout 10 seconds per sample, with preferences depending on the qualityof resolution required in a particular case. For example, in someresearch strategies, the very high sample throughputs can be effectivelyemployed to efficiently screen a sample or component thereof having aparticularly desired property (e.g., such as weight-average molecularweight). In short, the search can be accelerated for the particularproperty of research interest.

In other embodiments viscosity is measured at an averagesample-throughput of not more than 60 minutes per library, morepreferably not more than 10 minutes per library, and still morepreferably not more than 2 minutes per library. Even more preferred, theviscosity is measured at an average sample-throughput of not more than60 seconds per library, more preferably not more than 30 seconds perlibrary, and still more preferably not more than 10 seconds per library.

Calibration Methods and Standards

As desired the systems and methods of the present invention mayoptionally employ a calibration procedure. By way of example, acalibration standard is provided having a number of subcomponents thatdiffer with respect to viscosity. Such subcomponents are typicallyreferred to as “known standards” or, simply, “standards” that are wellcharacterized with respect to the calibrating property of interest. Theyare analyzed by the viscosity measuring apparatus of the presentinvention and the apparatus is adjusted as desired.

Other Screens

The present invention may be employed by itself or in combination withone or more other screening protocols (e.g., using the same instrumentwith an interchangeable test fixture, or a different instrument) for theanalysis of polymers, liquids or their consitituents. Withoutlimitation, examples of such screening techniques include thoseaddressed or identified in commonly-owned U.S. Pat. Nos. 6,182,499(McFarland et al); 6,175,409 B1 (Nielsen et al); 6,157,449 (Hajduk etal); 6,151,123 (Nielsen); 6,034,775 (McFarland et al); 5,959,297(Weinberg et al), 5,776,359 (Schultz et al.), all of which are herebyexpressly incorporated by reference herein.

It should be understood that the invention is not limited to the exactembodiment or construction which has been illustrated and described butthat various changes may be made without departing from the spirit andthe scope of the invention.

1. A method of screening a library of materials for viscosity, themethod comprising: providing a library of materials in a plurality ofwells defined on a common substrate; contacting members of said librarywith at least one capillary for permitting said materials to be passedthrough a tip portion of said capillary; applying a first force to saidmaterials; monitoring the relative flow resistance of said materials inresponse to said force, while said materials remain on said substrateand without the need to remove said materials from said substrate; andranking members of said library of materials based on the monitored flowresistance.
 2. The method of claim 1, further comprising heating saidliquids in said library.
 3. The method of claim 1, wherein said array ofmaterials includes a plurality liquid phase materials.
 4. The method ofclaim 3, wherein said liquid phase materials are in a media selectedfrom solutions, emulsions, dispersions or a mixture thereof.
 5. Themethod of claim 3, wherein said materials are polymers.
 6. The method ofclaim 1, wherein said library is disposed on a plural well microtiterplate and said measuring is done with each material entirely within itsrespective well of said microtiter plate.
 7. The method of claim 1,wherein said array includes at least 4 different liquid materials. 8.The method of claim 1, wherein said array includes at least 16 differentliquid materials.
 9. The method of claim 1 wherein said librarycomprises at least eight samples and at least about 50% of the samplesincluded in the library are different from each other.
 10. The method ofclaim 1 wherein said library comprises at least 16 samples and at least75% of said samples included in said library are different from eachother.
 11. The method of claim 1 wherein said library comprises at least48 samples and at least 90% of said samples included in the library aredifferent from each other.
 12. The method of claim 1 wherein saidsamples are polymerization product mixtures resulting frompolymerization reactions that are varied with respect to a factoraffecting polymerization.